How can I stop phosphenes
New mode of action for angina pectoris: ivabradine slows the heart rate
Ivabradine is the prototype of a new class of substances, the If channel inhibitors or If inhibitors. The new active ingredient only lowers the heart rate without affecting the conduction system or the muscle strength of the heart. As a result, ivabradine reduces the oxygen consumption of the heart muscle, increases coronary blood flow and protects against angina pectoris and ischemia. In contrast to beta-blockers, ivabradine lowers the heart rate both at rest and during exercise without causing negative inotropy or vasoconstriction. Ivabradine does not decrease blood pressure, cardiac contractility, or left ventricular function.
Selective inhibition of the If channel
Ivabradine selectively and specifically inhibits the flow of ions through the If channel in the pacemaker cells of the sinus node in the heart. The If current controls the spontaneous diastolic depolarization in the sinus node and regulates the heart rate.
The unspecific If channel lets a sodium / potassium ion stream through. It behaves unusually, "funny", hence the abbreviation If, because the ion current directed into the cell interior is activated by hyperpolarization and not by depolarization, as is the case with other known ion channels. The If channel mediates a positive chronotropic effect in response to sympathetic stimulation of the beta receptors.
If inhibitors such as ivabradine block open If channels and thus inhibit the flow of ions. As a result, they slow down the heart rate. The transfer times and blood pressure do not change. The cardiac effects are specific to the sinus node. Intra-atrial, atrioventricular (PQ time) or intraventricular conduction times are not influenced, nor are myocardial contractility (heart muscle strength) or ventricular repolarization (QTc time).
Specific lowering of the heart rate
In humans, ivabradine specifically and dose-dependently lowers the heart rate. At the usual recommended doses, the heart rate is lowered by approximately ten beats per minute at rest and under exertion. This leads to a reduction in cardiac work and myocardial oxygen consumption.
The approval is based on data from four double-blind, placebo-controlled studies comparing the antianginal and anti-ischemic effects of ivabradine with placebo, atenolol and amlodipine in 3,222 patients. In these studies, ivabradine at a dose of 5 or 7.5 mg twice daily significantly reduced the number of anginal episodes. Compared to placebo, ivabradine reduced the number of angina pectoris attacks and protected against ischemia in stable angina pectoris. In two large randomized, controlled, double-blind studies, a direct comparison with beta blockers and calcium antagonists demonstrated comparable effectiveness. In a phase III study, 300 patients with stable angina pectoris were treated with atenolol (50 mg, then 100 mg once daily) or ivabradine (5 mg, then 7.5 mg or 10 mg twice daily). Ivabradine was at least not inferior to atenolol in terms of antianginal efficacy; a treatment advantage may even be evident. The anti-anginal and anti-ischemic effects of ivabradine are also confirmed by two further clinical studies with over 2000 patients in which ivabradine was tested against the calcium antagonist amlodipine and the beta blocker atenolol. There were no significant differences between the groups in the antipectanginal effect, as measured by the patient's resilience. In all studies, treatment with ivabradine significantly reduced the number of angina attacks and the need for fast-acting nitrates.
Take twice a day
Ivabradine is available in film-coated tablets of 5 mg and 7.5 mg. The usually recommended starting dose of ivabradine is 5 mg twice a day. The tablets must be taken twice a day, i.e. once in the morning and once in the evening with meals.
Depending on the response to therapy, the dose can be increased to 7.5 mg twice daily after three to four weeks. If the heart rate continuously drops below 50 beats per minute (bpm) at rest during treatment or if the patient shows bradycardic symptoms such as dizziness, fatigue or hypotension, the dose may need to be increased gradually to 2.5 mg twice daily (half a 5 mg Tablet twice a day). Treatment should be interrupted if the heart rate remains below 50 bpm or if symptoms of bradycardia persist.
After ingestion, the substance is rapidly and almost completely absorbed. Maximum plasma levels are reached after a little over an hour on an empty stomach; absorption is delayed by around an hour through food. Because of the first-pass effect, bioavailability is around 40 percent. About 70 percent of ivabradine is bound to plasma protein. The substance is largely metabolized in the liver and intestines via cytochrome P450 3A4 (CYP3A4) and broken down with an effective half-life of eleven hours. Ivabradine is effective for 24 hours when taken twice daily.
Adverse effects on the retina: symptoms caused by light
Ivabradine can influence the retinal current Ih, which is very similar to the If current of the heart. It shortens the retina's response to bright light stimuli and is influenced by the temporary dissolution of the visual system. Under trigger conditions (e.g. rapid changes in light intensity), the partial inhibition of the Ih channel by ivabradine is the cause of the light-related symptoms that are occasionally observed in patients. Light-related symptoms (phosphenes) are described as temporary increased brightness in a limited area of the visual field.
These visual symptoms led to 0.7 percent of the patients discontinuing therapy in the studies. Symptomatic bradycardia occurred in 0.7 percent of the cases. Overall, ivabradine therapy is considered safe to date.
Not in bradycardia and severe hypotension
If the resting heart rate is less than 60 beats per minute before treatment, ivabradine must not be used, nor should it be used in cardiogenic shock, acute myocardial infarction, severe hypotension (< 90/50="" mmhg)="" und="" schwerer="" leberinsuffizienz.="" auch="" patienten="" mit="" sick-sinus-syndrom,="" mit="" sa-block,="" mit="" herzinsuffizienz="" nyha-klasse="" iii="" -="" iv,="" mit="" herzschrittmacher,="" mit="" instabiler="" angina="" pectoris,="" oder="" av-block="" 3.="" grades="" dürfen="" ivabradin="" nicht="" einnehmen.="">
Do not use with strong CYP3A4 inducers
Ivabradine is metabolised exclusively by CYP3A4 and is a very weak inhibitor of this cytochrome. Ivabradine has no effect on the metabolism and plasma concentrations of other CYP3A4 substrates (weak, moderate and strong inhibitors). CYP3A4 inhibitors and inducers can interact with ivabradine and affect its metabolism and pharmacokinetics to a clinically significant extent. CYP3A4 inhibitors increase ivabradine plasma concentrations while inducers decrease them. Elevated ivabradine plasma concentrations may be associated with the risk of excessive bradycardia. Therefore, the simultaneous use of strong CYP3A4 inhibitors such as azole antimycotics (ketoconazole, itraconazole), macrolide antibiotics (clarithromycin, erythromycin per os, josamycin, telithromycin), HIV protease inhibitors (nelfinavir, refitonazodir) is contraindicated.
When taken with grapefruit juice, ivabradine exposure was increased two-fold; therefore, the consumption of grapefruit juice should be restricted during treatment with ivabradine. CYP3A4 inducers (e.g. rifampicin, barbiturates, phenytoin, Hypericum perforatum [St. John's wort]) can reduce ivabradine exposure and its effectiveness. Concomitant use of CYP3A4 inducing drugs may require an adjustment of the ivabradine dose. The use of St. John's wort should be restricted during treatment with ivabradine.
Concomitant use of cardiovascular and non-cardiovascular QT prolonging medicinal products with ivabradine should be avoided, as QT prolongation can be increased by lowering the heart rate. If the combination appears necessary, careful cardiac monitoring is required. hel
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